JAK inhibitor therapy in a child with inherited usp18 deficiency

Fahad Alsohime; Marta Martin-Fernandez; Mohamad Hani Temsah; Majed Alabdulhafid; Tom Le Voyer; Malak Alghamdi; Xueer Qiu; Najla Alotaibi; Areej Alkahtani; Sofija Buta; Emmanuelle Jouanguy; Ayman Al-Eyadhy; Conor Gruber; Gamal M. Hasan; Fahad A. Bashiri; Rabih Halwani; Hamdy H. Hassan; Saleh Al-Muhsen; Nouf Alkhamis; Zobaida Alsum; Jean Laurent Casanova; Jacinta Bustamante; Dusan Bogunovic; Abdullah A. Alangari

doi:10.1056/NEJMoa1905633

JAK inhibitor therapy in a child with inherited usp18 deficiency

Fahad Alsohime, Marta Martin-Fernandez, Mohamad Hani Temsah, Majed Alabdulhafid, Tom Le Voyer, Malak Alghamdi, Xueer Qiu, Najla Alotaibi, Areej Alkahtani, Sofija Buta, Emmanuelle Jouanguy, Ayman Al-Eyadhy, Conor Gruber, Gamal M. Hasan, Fahad A. Bashiri, Rabih Halwani, Hamdy H. Hassan, Saleh Al-Muhsen, Nouf Alkhamis, Zobaida AlsumJean Laurent Casanova, Jacinta Bustamante, Dusan Bogunovic, Abdullah A. Alangari

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70 Scopus citations

Abstract

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery.

Original language	English
Pages (from-to)	256-265
Number of pages	10
Journal	New England Journal of Medicine
Volume	382
Issue number	3
DOIs	https://doi.org/10.1056/NEJMoa1905633
State	Published - 16 Jan 2020

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Alsohime, F., Martin-Fernandez, M., Temsah, M. H., Alabdulhafid, M., Le Voyer, T., Alghamdi, M., Qiu, X., Alotaibi, N., Alkahtani, A., Buta, S., Jouanguy, E., Al-Eyadhy, A., Gruber, C., Hasan, G. M., Bashiri, F. A., Halwani, R., Hassan, H. H., Al-Muhsen, S., Alkhamis, N., ... Alangari, A. A. (2020). JAK inhibitor therapy in a child with inherited usp18 deficiency. New England Journal of Medicine, 382(3), 256-265. https://doi.org/10.1056/NEJMoa1905633

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title = "JAK inhibitor therapy in a child with inherited usp18 deficiency",

abstract = "Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery.",

author = "Fahad Alsohime and Marta Martin-Fernandez and Temsah, {Mohamad Hani} and Majed Alabdulhafid and {Le Voyer}, Tom and Malak Alghamdi and Xueer Qiu and Najla Alotaibi and Areej Alkahtani and Sofija Buta and Emmanuelle Jouanguy and Ayman Al-Eyadhy and Conor Gruber and Hasan, {Gamal M.} and Bashiri, {Fahad A.} and Rabih Halwani and Hassan, {Hamdy H.} and Saleh Al-Muhsen and Nouf Alkhamis and Zobaida Alsum and Casanova, {Jean Laurent} and Jacinta Bustamante and Dusan Bogunovic and Alangari, {Abdullah A.}",

note = "Publisher Copyright: {\textcopyright} 2020 Massachusetts Medical Society.",

year = "2020",

month = jan,

day = "16",

doi = "10.1056/NEJMoa1905633",

language = "English",

volume = "382",

pages = "256--265",

journal = "New England Journal of Medicine",

issn = "0028-4793",

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Alsohime, F, Martin-Fernandez, M, Temsah, MH, Alabdulhafid, M, Le Voyer, T, Alghamdi, M, Qiu, X, Alotaibi, N, Alkahtani, A, Buta, S, Jouanguy, E, Al-Eyadhy, A, Gruber, C, Hasan, GM, Bashiri, FA, Halwani, R, Hassan, HH, Al-Muhsen, S, Alkhamis, N, Alsum, Z, Casanova, JL, Bustamante, J, Bogunovic, D & Alangari, AA 2020, 'JAK inhibitor therapy in a child with inherited usp18 deficiency', New England Journal of Medicine, vol. 382, no. 3, pp. 256-265. https://doi.org/10.1056/NEJMoa1905633

TY - JOUR

T1 - JAK inhibitor therapy in a child with inherited usp18 deficiency

AU - Alsohime, Fahad

AU - Martin-Fernandez, Marta

AU - Temsah, Mohamad Hani

AU - Alabdulhafid, Majed

AU - Le Voyer, Tom

AU - Alghamdi, Malak

AU - Qiu, Xueer

AU - Alotaibi, Najla

AU - Alkahtani, Areej

AU - Buta, Sofija

AU - Jouanguy, Emmanuelle

AU - Al-Eyadhy, Ayman

AU - Gruber, Conor

AU - Hasan, Gamal M.

AU - Bashiri, Fahad A.

AU - Halwani, Rabih

AU - Hassan, Hamdy H.

AU - Al-Muhsen, Saleh

AU - Alkhamis, Nouf

AU - Alsum, Zobaida

AU - Casanova, Jean Laurent

AU - Bustamante, Jacinta

AU - Bogunovic, Dusan

AU - Alangari, Abdullah A.

PY - 2020/1/16

Y1 - 2020/1/16

N2 - Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery.

AB - Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery.

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U2 - 10.1056/NEJMoa1905633

DO - 10.1056/NEJMoa1905633

M3 - Article

C2 - 31940699

AN - SCOPUS:85077940751

SN - 0028-4793

VL - 382

SP - 256

EP - 265

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 3

ER -

JAK inhibitor therapy in a child with inherited usp18 deficiency

Abstract

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